This invention is directed to proteinase (protease) inhibitors, and more particularly to xcex1-amino-xcex2-sulfonyl carbocyclo, heterocyclo, aryl, or heteroaryl hydroxamic acid compounds that, inter alia, inhibit the activity of matrix metalloproteinases, compositions of those inhibitors, intermediates for the syntheses of those compounds, processes for the preparation of the compounds and processes for treating pathological conditions associated with pathological matrix metalloproteinase activity.
Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
Under normal conditions, connective tissue Turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.
Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function is the zinc metalloproteinases (metalloproteases, or MMPs).
The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.
The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimer""s Disease; coronary thrombosis and bone disease. Defective injury repair processes can also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.
Matrix metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF) and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-xcex1, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal.
TNF-xcex1 convertase is a metalloproteinase involved in the formation of active TNF-xcex1. Inhibition of TNF-xcex1 convertase inhibits production of active TNF-xcex1. Compounds that inhibit both MMPs activity have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466, WO 97/20824 and EP 0 780 386 A1. There remains a need for effective MMP and TNF-xcex1 convertase inhibiting agents. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)).
MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (xcex2-Amyloid Precursor Protein) to the amyloid plaque and inactivation of xcex11-protease inhibitor (xcex11-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as xcex11-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin (MMP-3), gelatinase (MMP-2), gelatinase B (MMP-9) or collagenase III (MMP-13) are the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile.
Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation in inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP), xcex12-macroglobulin and their analogs or derivatives. These are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.
Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).
One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
In view of the importance of hydroxamate MMP inhibitor compounds in the treatment of several diseases and the lack of enzyme specificity exhibited by two of the more potent drugs now in clinical trials, it would be a great benefit if hydroxamates of greater enzyme specificity could be found. This would be particularly the case if the hydroxamate inhibitors exhibited strong inhibitory activity against one or more of MMP-2, MMP-9 or MMP-13 that are associated with several pathological conditions, while at the same time exhibiting limited inhibition of MMP-1, an enzyme that is relatively ubiquitous and as yet not associated with any pathological condition. It would also be beneficial if a compound that inhibited one or more of the above MMPs, while sparing MMP-1, also did not inhibit production of TNF. The disclosure that follows describes one family of hydroxamate MMP inhibitors that exhibit those desirable activities.
The present invention is directed to a family of molecules that among other properties inhibit matrix metalloprotease (MMP) activity, and particularly inhibit the activity of one or more of MMP-2, MMP-9, or MMP-13, while generally exhibiting little activity against MMP-1. A contemplated compound also exhibits little inhibition of the production of TNF. The present invention is also directed to processes for preparing a contemplated compound and for treating a mammal having a condition associated with pathological matrix metalloprotease activity.
Briefly, one embodiment of the present invention is directed to an xcex1-amino-xcex2-sulfonyl carbocyclo, heterocyclo, aryl, or heteroaryl hydroxamic acid compound that is active as a matrix metalloprotease enzyme inhibitor. That compound corresponds in structure to Formula A. 
wherein
R2 is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy, halo-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxymethyl, aryl, aryl C1-C4 hydrocarbyl, aminomethyl, (Nxe2x80x94C1-C3 hydrocarbyl)aminomethyl, (N,N-di-C1-C3 hydrocarbyl)aminomethyl, (N-morpholino)methyl, (N-pyrrolidino)methyl, or (N-thiomorpholino)methyl group. R2 is preferably a hydrido, hydroxy, hydroxymethyl, methoxymethyl or methyl-N-morpholinyl group.
R1 is a substituent that contains an optionally substituted 5- or 6-membered carbocyclo, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2xe2x80x94 group that has a length of an extended pentyl group and less than about that of an extended eicosyl group, and preferably having a length that is longer than an extended hexyl group and less than that of an extended stearyl group. In addition, R1 defines a three-dimensional volume upon rotation about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings.
R6 and R7 are independently selected from the group consisting of a hydrido, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, heterocyclocarbonyl, heterocycloalkylcarbonyl, aryloxycarbonylaminoalkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, perfluoroalkylcarbonyl, trifluoromethylalkylcarbonyl, alkylthioalkylcarbonyl, arylthioalkylcarbonyl, aralkylthioalkylcarbonyl, heteroaralkylthioalkylcarbonyl, or a sulfoxide or sulfone of any of said thio substituents, alkylsulfonyl, arylsulfonyl, and an aminocarbonylalkyl or aminocarbonylalkylcarbonyl group
wherein the aminocarbonylalkyl or aminocarbonylalkylcarbonyl nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted-alkylaminoalkyl group, or (iv) that carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group, or
R6 and R7 together with the depicted nitrogen atom form a saturated or unsaturated cyclic imide substituent in which the ring contains five to eight atoms.
R20 is (a) xe2x80x94Oxe2x80x94R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b) xe2x80x94NR13xe2x80x94Oxe2x80x94R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl, and R13 is a hydrido, C1-C6-alkyl or benzyl group, or (c) xe2x80x94NR13xe2x80x94Oxe2x80x94R14, where R13 is as before and R14 is a hydrido, a pharmaceutically acceptable cation or C(W)R15 group, where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
A 5- or 6-membered carbocyclo, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group that constitutes an R1 group whose 5- or 6-membered carbocyclo, heterocyclo, aryl or heteroaryl radical of R1 is itself optionally substituted with an xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y substituent. In such an xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y substituent, A is selected from the group consisting of
(1) xe2x80x94Oxe2x80x94;
(2) xe2x80x94Sxe2x80x94;
(3) xe2x80x94NRkxe2x80x94;
(4) xe2x80x94COxe2x80x94N(Rk) or xe2x80x94N(Rk)xe2x80x94COxe2x80x94;
(5) xe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94;
(6) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94;
(7) xe2x80x94HCxe2x95x90CHxe2x80x94;
(8) xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94;
(9) xe2x80x94Cxe2x89xa1Cxe2x80x94;
(10) xe2x80x94Nxe2x95x90Nxe2x80x94;
(11) xe2x80x94NHxe2x80x94NHxe2x80x94;
(12) xe2x80x94CSxe2x80x94N(Rk)xe2x80x94 or xe2x80x94N(Rk)xe2x80x94CSxe2x80x94;
(13) xe2x80x94CH2xe2x80x94;
(14) xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94;
(15) xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94;
(16) xe2x80x94SOxe2x80x94; and
(17) xe2x80x94SO2xe2x80x94; or
(18) A is absent and R is directly bonded to the depicted SO2-bonded 5- or 6-membered ring group.
The moiety R is selected from the group consisting of alkyl, alkoxy, halo, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxy-alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group.
The group E is selected from the group consisting of
(1) xe2x80x94CO(Rg)xe2x80x94 or xe2x80x94(Rg)COxe2x80x94;
(2) xe2x80x94CON(Rk)xe2x80x94 or xe2x80x94(Rk)NCOxe2x80x94;
(3) xe2x80x94COxe2x80x94;
(4) xe2x80x94SO2xe2x80x94Rg or xe2x80x94RgSO2xe2x80x94;
(5) xe2x80x94SO2xe2x80x94;
(6) xe2x80x94N(Rk)xe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94N(Rk)xe2x80x94; or
(7) E is absent and R is bonded directly to Y; and
Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Rcoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
Preferably, an xe2x80x94R1 substituent is a substituent xe2x80x94Gxe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y in which
G is an aryl or heteroaryl group;
the substituent A is selected from the group consisting of
(1) xe2x80x94Oxe2x80x94;
(2) xe2x80x94Sxe2x80x94;
(3) xe2x80x94NRkxe2x80x94;
(4) xe2x80x94COxe2x80x94N(Rk) or xe2x80x94N(Rk)xe2x80x94COxe2x80x94;
(5) xe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94;
(6) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94;
(7) xe2x80x94HCxe2x95x90CHxe2x80x94;
(8) xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94;
(9) xe2x80x94Cxe2x89xa1Cxe2x80x94;
(10) xe2x80x94Nxe2x95x90Nxe2x80x94;
(11) xe2x80x94NHxe2x80x94NHxe2x80x94;
(12) xe2x80x94CSxe2x80x94N(Rk)xe2x80x94 or xe2x80x94N(Rk)xe2x80x94CSxe2x80x94;
(13) xe2x80x94CH2xe2x80x94;
(14) xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94;
(15) xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94;
(16) xe2x80x94SOxe2x80x94; and
(17) xe2x80x94SO2xe2x80x94; or
(18) A is absent and R is directly bonded to the N-heterocyclo group, G.
The moiety R is selected from the group consisting of alkyl, alkoxy, halo, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group.
The moiety E is selected from the group consisting of
(1) xe2x80x94CO(Rg)xe2x80x94 or xe2x80x94(Rg)COxe2x80x94;
(2) xe2x80x94CON(Rk)xe2x80x94 or xe2x80x94(Rk)NCOxe2x80x94;
(3) xe2x80x94COxe2x80x94;
(4) xe2x80x94SO2xe2x80x94Rgxe2x80x94 or xe2x80x94Rgxe2x80x94SO2xe2x80x94;
(5) xe2x80x94SO2xe2x80x94;
(6) xe2x80x94N(Rk) xe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94N(Rk)xe2x80x94; or
(7) E is absent and R is bonded directly to Y; and
the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Rcoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group; and wherein
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl or arylalkyloxycarbonyl group;
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen (halo; F, Cl, Br, I), aryl, alkoxy, cyano, and RdReamino group;
Rg is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhRi-aminocarbonyloxy, RhRi-aminocarbonyl, RhRi-aminoalkanoyl, hydroxyaminocarbonyl, RhRi-aminosulfonyl, RhRi-aminocarbonyl(Rh)amino, trifluoromethylsulfonyl-(Rh)amino, heteroarylsulfonyl(Rh)amino, arylsulfonyl(Rh)amino, arylsulfonyl(Rh)aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl(Rh)aminosulfonyl, and an alkylsulfonyl(Rh)aminocarbonyl substituent;
wherein Rh is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups is optionally substituted by one or two groups independently selected from Rj substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups;
Ri is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups are optionally substituted by one or two Rj substituents;
Rj is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of an alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group; and
Rk is selected from hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkylsulfonyl, and Ra, Rc, Rd, and Rg are as defined hereinbefore.
A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering a compound corresponding in structure to Formula B that selectively inhibits one or more MMPS, while exhibiting less activity against at least MMP-1 in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition. A contemplated compound also does not substantially inhibit the production of TNF. 
wherein R1, R2, R6, R7, R13, and R14 are as defined before. Preferably, R2, R6, and R13 are hydrido, and R7 is R7A, wherein R7A is selected from the group consisting of an alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aminoalkylcarbonyl, aminoaralkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, alkoxycarbonylaminoaralkylcarbonyl, cycloalkoxycarbonylaminoalkylcarbonyl, cycloalkoxycarbonylaminoaralkylcarbonyl, aryloxycarbonylaminoalkylcarbonyl, aryloxycarbonylaminoaralkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, heteroaryloxycarbonylaminoalkylcarbonyl and a heteroaryloxycarbonylaminoaralkylcarbonyl group.
An intermediate compound in the preparation of a particularly preferred compound of Formula A is also contemplated. Such a compound has a structure that corresponds to formula C, below. 
wherein R2, R6, R7 and R20 are as before described and D is a nucleophilically-displacable leaving group such as xe2x80x94F or xe2x80x94NO2.
A particularly preferred intermediate for use i preparing a contemplated MMP inhibitor corresponds in structure to Formula D, below, wherein R1, R2, R6, R7 and R13 are as before described. 
Among the several benefits and advantages of the present invention are the provision of compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.
More particularly, a benefit of this invention is the provision of a compound and composition effective for inhibiting metalloproteinases, particularly MMP-13 and/or MMP-2, associated with pathological conditions such as, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer""s Disease, coronary thrombosis, plaque formation and bone disease.
An advantage of the invention is the provision of a method for preparing such compounds and compositions. Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
Another benefit of the invention is that a contemplated compound typically exhibits about equal to greater inhibition of MMP-2 as compared to MMP-13, while maintaining sparing (lessened) inhibitory activity against MMP-1.
Another advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-13 and MMP-2 associated with such conditions with minimal side effects resulting from inhibition of other proteinases such as MMP-1, whose activity is necessary or desirable for normal body function.
Yet another advantage of a contemplated compound is the selectivity with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release that provides the physician with another factor to help select the best drug for a particular patient. While not wishing to be bound by theory, it is believed that there are several factors to this type of selectivity to be considered.
The first is that presence of tumor necrosis factor can be desirable for the control of cancer in the organism, so long as TNF is not present in a toxic excess. Thus, uncontrolled inhibition of release of TNF can be counterproductive and actually can be considered an adverse side effect even in cancer patients. In addition, selectivity with respect to inhibition of the release of the tumor necrosis factor receptor can also be desirable. The presence of that receptor can be desirable for maintaining a controlled tumor necrosis level in the mammal by binding excess TNF.
Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.
In accordance with the present invention, it has been found that certain xcex1-amino-xcex2-sulfonyl carbocyclo, heterocyclo, aryl or heteroaryl hydroxamic acids (hydroxamates) are effective, inter alia, for inhibition of matrix metalloproteinases (xe2x80x9cMMPsxe2x80x9d) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain xcex1-amino-xcex2-sulfonyl carbocyclo, heterocyclo, aryl or heteroaryl hydroxamic acid compounds are effective for inhibition of collagenase III (MMP-13) and also gelatinase A (MMP-2), which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity.
Moreover, it has been discovered that many of these xcex1-amino-xcex2-sulfonyl carbocyclo, heterocyclo, aryl or heteroaryl hydroxamic acids are selective in the inhibition of MMPs associated with diseased conditions without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that particularly preferred the xcex1-amino-xcex2-sulfonyl carbocyclo, heterocyclo, aryl or heteroaryl hydroxamic acid compounds are particularly active in inhibiting of MMP-13 and/or MMP-2, while having a limited or minimal effect on MMP-1. This point is discussed in detail hereinafter and is illustrated in the Inhibition Table hereinafter.
One embodiment of the present invention is directed to a xcex1-amino-xcex2-sulfonyl carbocyclo, heterocyclo, aryl or heteroaryl hydroxamic acid compound, a pharmaceutically acceptable salt of such a compound that can act as a matrix metalloprotease enzyme inhibitor, a precursor to such a compound or a pro-drug form of such a compound. A contemplated compound corresponds in structure to Formula A. 
wherein
R2 is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxymethyl, aryl, aryl C1-C4 hydrocarbyl, aminomethyl, (Nxe2x80x94C1-C3 hydrocarbyl)aminomethyl, (N,N-di-C1-C3 hydrocarbyl)aminomethyl, (N-morpholino)methyl, (N-pyrrolidino)methyl, or (N-thiomorpholino)methyl group. R2 is preferably a hydrido, hydroxy, hydroxymethyl, methoxymethyl, C1-C4 hydrocarbyl (e.g. methyl), aryl(phenyl) or methyl-N-morpholinyl group, with phenyl or C1-C4 hydrocarbyl being more preferred;
R1 is a substituent that contains an optionally substituted 5- or 6-membered carbocyclo, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2xe2x80x94 group that has a length of an extended pentyl group and less than about that of an extended eicosyl group. In addition, R1 defines a three-dimensional volume that upon rotation about an axis drawn through the SO2xe2x80x94bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2xe2x80x94bonded 1-position and the center of 3,4-bond of a 5-membered ring radical whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings; R1 preferably has a length that is greater than an that of an extended hexyl group and less than that of an extended stearyl group.
R6 and R7 are independently selected from the group consisting of a hydrido, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, heterocyclocarbonyl, heterocycloalkylcarbonyl, aryloxycarbonylaminoalkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, perfluoroalkylcarbonyl, trifluoromethylalkylcarbonyl, alkylthioalkylcarbonyl, arylthioalkylcarbonyl, aralkylthioalkylcarbonyl, heteroaralkylthioalkylcarbonyl, or a sulfoxide or sulfone of any of said thio substituents, alkylsulfonyl, arylsulfonyl, and an aminocarbonylalkyl or aminocarbonylalkylcarbonyl group
wherein the aminocarbonylalkyl or aminocarbonylalkylcarbonyl nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted-alkylaminoalkyl group, or (iv) that carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group, or
R6 and R7 together with the depicted nitrogen atom form a saturated or unsaturated cyclic imide substituent in which the ring contains five to eight atoms;
R6 is preferably hydrido, and R7 is preferably an alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aminoalkylcarbonyl or a substituted aminoalkylcarbonyl group such as an alkoxycarbonylaminoalkylcarbonyl, cycloalkoxycarbonylaminoalkylcarbonyl, aryloxycarbonylaminoalkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, or heteroaryloxycarbonylaminoalkylcarbonyl group;
R20 is (a) xe2x80x94Oxe2x80x94R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b) xe2x80x94NR13xe2x80x94Oxe2x80x94R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl, and R13 is a hydrido, C1-C6-alkyl or benzyl group, or (c) xe2x80x94NR13xe2x80x94Oxe2x80x94R14, where R13 is as before and R14 is a hydrido, a pharmaceutically acceptable cation or C(W)R15 group, where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
A 5- or 6-membered carbocyclo, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2xe2x80x94 group that constitutes an R1 group that is itself optionally substituted with an xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y substituent. In such an xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y substituent, A is selected from the group consisting of
(1) xe2x80x94Oxe2x80x94;
(2) xe2x80x94Sxe2x80x94;
(3) xe2x80x94NRkxe2x80x94;
(4) xe2x80x94COxe2x80x94N(Rk) or xe2x80x94N(Rk)xe2x80x94COxe2x80x94;
(5) xe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94;
(6) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94;
(7) xe2x80x94HCxe2x95x90CHxe2x80x94;
(8) xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94;
(9) xe2x80x94Cxe2x89xa1Cxe2x80x94;
(10) xe2x80x94Nxe2x95x90Nxe2x80x94;
(11) xe2x80x94NHxe2x80x94NHxe2x80x94;
(12) xe2x80x94CSxe2x80x94N(Rk)xe2x80x94 or xe2x80x94N(Rk)xe2x80x94CSxe2x80x94;
(13) xe2x80x94CH2xe2x80x94;
(14) xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94;
(15) xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94;
(16) xe2x80x94SOxe2x80x94; and
(17) xe2x80x94SO2xe2x80x94; or
(18) A is absent and R is directly bonded to the depicted SO2xe2x80x94bonded 5- or 6-membered ring group.
The moiety R is selected from the group consisting of alkyl, alkoxy, halo, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxy-alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group.
The group E is selected from the group consisting of
(1) xe2x80x94CO(Rg)xe2x80x94 or xe2x80x94(Rg)COxe2x80x94;
(2) xe2x80x94CON(Rk)xe2x80x94 or xe2x80x94(Rk)NCOxe2x80x94;
(3) xe2x80x94COxe2x80x94;
(4) xe2x80x94SO2xe2x80x94Rg or xe2x80x94RgSO2xe2x80x94;
(5) xe2x80x94SO2xe2x80x94;
(6) xe2x80x94N(Rk)xe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94N(Rk)xe2x80x94; or
(7) E is absent and R is bonded directly to Y; and
Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Rcoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, tri-fluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
Preferably, an xe2x80x94R1 substituent is a substituent xe2x80x94Gxe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y in which
G is an aryl or heteroaryl group;
the substituent A is selected from the group consisting of
(1) xe2x80x94Oxe2x80x94;
(2) xe2x80x94Sxe2x80x94;
(3) xe2x80x94NRkxe2x80x94;
(4) xe2x80x94COxe2x80x94N(Rk) or xe2x80x94N(Rk)xe2x80x94COxe2x80x94;
(5) xe2x80x94COxe2x80x94xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94;
(6) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94;
(7) xe2x80x94HCxe2x95x90CHxe2x80x94;
(8) xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94;
(9) xe2x80x94Cxe2x89xa1Cxe2x80x94;
(10) xe2x80x94Nxe2x95x90Nxe2x80x94;
(11) xe2x80x94NHxe2x80x94NHxe2x80x94;
(12) xe2x80x94CSxe2x80x94N(Rk)xe2x80x94 or xe2x80x94N(Rk)xe2x80x94CSxe2x80x94;
(13) xe2x80x94CH2xe2x80x94;
(14) xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94;
(15) xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94;
(16) xe2x80x94SOxe2x80x94; and
(17) xe2x80x94SO2xe2x80x94; or
(18) A is absent and R is directly bonded to the N-heterocyclo group, G.
The moiety R is selected from the group consisting of alkyl, alkoxy, halo, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group.
The moiety E is selected from the group consisting of
(1) xe2x80x94CO(Rg)xe2x80x94 or xe2x80x94(Rg)COxe2x80x94;
(2) xe2x80x94CON(Rk)xe2x80x94 or xe2x80x94(Rk)NCOxe2x80x94;
(3) xe2x80x94COxe2x80x94;
(4) xe2x80x94SO2xe2x80x94Rgxe2x80x94 or xe2x80x94Rgxe2x80x94SO2xe2x80x94;
(5) xe2x80x94SO2xe2x80x94;
(6) xe2x80x94N(Rk)xe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94N(Rk)xe2x80x94; or
(7) E is absent and R is bonded directly to Y; and
the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Rcoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group; and wherein
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl or arylalkyloxycarbonyl group;
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen (halo; F, Cl, Br, I), aryl, alkoxy, cyano, and RdReamino group;
Rg is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhRi-aminocarbonyloxy, RhRi-aminocarbonyl, RhRi-aminoalkanoyl, hydroxyaminocarbonyl, RhRi-aminosulfonyl, RhRi-aminocarbonyl(Rh)amino, trifluoromethylsulfonyl-(Rh)amino, heteroarylsulfonyl(Rh)amino, arylsulfonyl(Rh)amino, arylsulfonyl(Rh)aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl(Rh)aminosulfonyl, and an alkylsulfonyl(Rh)aminocarbonyl substituent;
wherein Rh is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups is optionally substituted by one or two groups independently selected from Rj substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups;
Ri is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups are optionally substituted by one or two Ri substituents;
Rj is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of an alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group; and
Rk is selected from hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkylsulfonyl, and Ra, Rc, Rd, and Rg are as defined hereinbefore.
A more preferred group of contemplated compounds corresponds in structure to Formula B1, below, 
wherein R1 and R14 are as defined before, and R7A is selected from the group consisting of an alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aminoalkylcarbonyl, aminoaralkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, alkoxycarbonylaminoaralkylcarbonyl, cycloalkoxycarbonylaminoalkylcarbonyl, cycloalkoxycarbonylaminoaralkylcarbonyl, aryloxycarbonylaminoalkylcarbonyl, aryloxycarbonylaminoaralkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, heteroaryloxycarbonylaminoalkylcarbonyl and a heteroaryloxycarbonylaminoaralkylcarbonyl group.
An intermediate compound useful in the preparation of a particularly preferred compound of Formula A is also contemplated. One such intermediate has a structure that corresponds to formula C, below. 
wherein R2, R6, R7 and R20 are as before described and D is a nucleophilically-displacable leaving group such as xe2x80x94F or xe2x80x94NO2. Here, R20is usually xe2x80x94Oxe2x80x94R21, wherein R21 is typically hydrido.
Another particularly preferred intermediate for use in preparing a contemplated MMP inhibitor corresponds in structure to Formula D, below, wherein R1, R2, R6, R7 and R13 are as before described. 
Preferably in Formula D, R2, R6 and R13 are preferably hydrido, and R7 is preferably R7A.
When examined along its longest chain of atoms, an R1 substituent, including its own substituent when present, has a total length that is greater than that of a fully extended saturated chain of five carbon atoms (a pentyl group); i.e., a length of a hexyl chain in staggered conformation or longer. An R1 substituent also has a length that is less than that of a fully extended saturated chain of about 20 carbons (an eicosyl group). Preferably, that length is greater than that of a hexyl group and shorter than that of a stearyl group, even though many more atoms may be present in ring structures or substituents.
Looked at more generally, and aside from specific moieties from which it is constructed, an R1 substituent (radical, group or moiety) has a length of a pentyl group or greater. Such an R1 substituent also has a length that is less than that of an eicosyl group. That is to say that a R1 is a substituent having a length greater than that of a fully extended saturated five carbon chain and shorter than that of a fully extended saturated twenty carbon chain, and more preferably, a length greater than that of a hexyl group and less than that of a stearyl group. The radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms of a ring where necessary. Each atom in the chain, e.g. carbon, oxygen or nitrogen, is presumed to be carbon for ease in calculation.
Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by presuming, as is done here, that all atoms have bond lengths of saturated carbon, that unsaturated and aromatic bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a 4-phenyl or 4-pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a 4-halophenyl group has the length of a five carbon chain and biphenyl group has the length of about an eight carbon chain using a contemplated measurement mode.
In addition, an R1 substituent, upon rotation about an axis drawn through the SO2-xe2x80x94bonded 1-position and the 4-position of a 6-membered ring radical or the SO2-xe2x80x94 bonded 1-position and through the 3,4 bond of a 5-membered ring radical defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about the width of two phenyl rings in a direction transverse to that axis to rotation.
When utilizing this width or volume criterion, a fused ring system such as a naphthyl or purinyl radical is considered to be a 6- or 5-membered ring that is substituted at appropriate positions numbered from the SO2-linkage that is deemed to be at the 1-position as discussed before. Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R1 radical as to width when examined using the above rotational width criterion. On the other hand, a 1-naphthyl group or a 7- or 9-purinyl group is too large upon rotation and is excluded.
As a consequence of these length and width requirements, R1 substituents such as 4-(phenyl)phenyl[biphenyl], 4-(4xe2x80x2-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl[4-(phenylthio)phenyl], 4-(phenylazo)phenyl 4-(phenylureido)phenyl, 4-(anilino)phenyl, 4-(nicotinamido)phenyl, 4-(isonicotinamido)phenyl, 4-(picolinamido)phenyl and 4-(benzamido)phenyl are among particularly preferred R1 substituents, with 4-(phenoxy)phenyl and 4-(thiophenyl)phenyl being most preferred.
An SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is a 5- or 6-membered single-ring that is itself substituted with one other substituent, R4. The SO2-linked single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is R4-substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring. The cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical to which R4 is bonded in some embodiments is preferably a phenyl group, so that R1 is preferably PhR4 in which R4 is bonded at the 4-position of the SO2-linked phenyl (Ph) radical, and in which R4 can itself be optionally substituted as is discussed hereinafter. In other embodiments, a heterocyclo or heteroaryl radical is preferred over a phenyl radical, with the R4 substituent being linked at the 4-position relative to the bond between the ring and the SO2 group.
A contemplated R4 substituent can be a single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group or another substituent having a chain length of 3 to about 14 carbon atoms such as a hydrocarbyl or hydrocarbyloxy group [e.g., C3-C14 hydrocarbyl or Oxe2x80x94C2-C14 hydrocarbyl], a phenyl group, a phenoxy group [xe2x80x94OC6H5], a thiophenoxy group [phenylsulfanyl; xe2x80x94SC6H5], an anilino group [xe2x80x94NHC6H5], a phenylazo group [xe2x80x94N2C6H5], a phenylureido group [aniline carbonylamino; xe2x80x94NHC(O)NHxe2x80x94C6H5], a benzamido group [xe2x80x94NHC(O)C6H5], a nicotinamido group [3-NHC(O)C5H4N], an isonicotinamido group [4-NHC(O)C5H4N], or a picolinamido group [2-NHC(O)C5H4N]. Additionally contemplated R4 substituent groups include a heterocyclo, heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclo-hydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbyl-thiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, or a heteroarylthio group.
A contemplated R4 substituent can itself also be substituted with one or more substituent radicals at the meta- or para-position or both of a six-membered ring with a single atom or a substituent containing a longest chain of up to ten atoms, excluding hydrogen. Exemplary substituent radicals include a halo, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N,N-disubstituted aminohydrocarbyl group wherein the substituent(s) on the nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group.
Compounds that are intermediates in the preparation of a MMP-inhibiting compound are also contemplated by this invention. One preferred intermediate corresponds in structure to Formula C, below, 
wherein R2, R6, R7 and R20 are as before described and D is a nucleophilically-displacable leaving group such as xe2x80x94F or xe2x80x94NO2. R2 and R6 are preferably hydrido here, R7 is preferably R7A, and R20 is preferably xe2x80x94Oxe2x80x94R21, wherein R21 is hydrido.
Another preferred intermediate compound corresponds in structure to Formula D, below, structure to Formula D, below, wherein R1, R2, R6, R7 and R13 are as before described. 
In preferred practice for a compound of Formula D, R2, R6 and R13 are hydrido, and R7 is R7A.
Table 1 through Table 9, below, illustrate several synthesized compounds that are contemplated by this invention and are useful in a contemplated process. Inhibition data for those compounds in in vitro assays against MMP-1 and MMP-13 are provided hereinafter.
As utilized herein, the term xe2x80x9calkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to about 12 carbon atoms preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include ethenyl(vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.
The term xe2x80x9calkynylxe2x80x9d, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing 2 to about 12 carbon atoms, preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
The term xe2x80x9ccarbonylxe2x80x9d or xe2x80x9coxoxe2x80x9d, alone or in combination, means a xe2x80x94C(xe2x95x90O)xe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted. The term carbonyl is also intended to encompass a hydrated carbonyl group xe2x80x94C(OH)2xe2x80x94.
The term xe2x80x9cthiolxe2x80x9d or xe2x80x9csulfhydrylxe2x80x9d, alone or in combination, means a xe2x80x94SH group. The term xe2x80x9cthioxe2x80x9d or xe2x80x9cthiaxe2x80x9d, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.
The term xe2x80x9caminoxe2x80x9d, alone or in combination, means an amine or xe2x80x94NH2 group whereas the term mono-substituted amino, alone or in combination, means a substituted amine xe2x80x94N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a xe2x80x94N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.
Amines, amino groups and amides are compounds that can be designated as primary (Ixc2x0), secondary (IIxc2x0) or tertiary (IIIxc2x0) or unsubstituted, mono-substituted or N,N-disubstituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (ammonium)(IVxc2x0) means a nitrogen with four substituents [xe2x80x94N+(substituent)4] that is positively charged and accompanied by a counter ion, whereas N-oxide means one substituent is oxygen and the group is represented as [xe2x80x94N+(substituent)3xe2x80x94Oxe2x88x92]; i.e., the charges are internally compensated.
The term xe2x80x9ccyanoxe2x80x9d, alone or in combination, means a xe2x80x94C-triple bond-N (xe2x80x94Cxe2x89xa1N) group. The term xe2x80x9cazidoxe2x80x9d, alone or in combination, means a xe2x80x94N-triple bond-N (xe2x80x94Nxe2x89xa1N) group. The term xe2x80x9chydroxylxe2x80x9d, alone or in combination, means a xe2x80x94OH group. The term xe2x80x9cnitroxe2x80x9d, alone or in combination, means a xe2x80x94NO2 group. The term xe2x80x9cazoxe2x80x9d, alone or in combination, means a xe2x80x94Nxe2x95x90Nxe2x80x94 group wherein the bonds at the terminal positions can be independently substituted.
The term xe2x80x9chydrazinoxe2x80x9d, alone or in combination, means a xe2x80x94NHxe2x80x94NHxe2x80x94 group wherein the depicted remaining two bonds (valences) can be independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.
The term xe2x80x9csulfonylxe2x80x9d, alone or in combination, means a xe2x80x94SO2xe2x80x94 group wherein the depicted remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfoxidoxe2x80x9d, alone or in combination, means a xe2x80x94SOxe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted.
The term xe2x80x9csulfonexe2x80x9d, alone or in combination, means a xe2x80x94SO2xe2x80x94 group wherein the depicted remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfenamidexe2x80x9d, alone or in combination, means a xe2x80x94SONxe2x95x90 group wherein the remaining three depicted bonds (valences) can be independently substituted. The term xe2x80x9csulfidexe2x80x9d, alone or in combination, means a xe2x80x94Sxe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, means a cyclic alkyl radical that contains 3 to about 8 carbon atoms. The term xe2x80x9ccycloalkylalkylxe2x80x9d means an alkyl radical as defined above that is substituted by a cycloalkyl radical containing 3 to about 8, preferably 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
A heterocyclic (heterocyclo) or heterocyclo portion of a heterocyclocarbonyl, heterocyclooxycarbonyl, heterocycloalkoxycarbonyl, or heterocycloalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one or more hetero atoms selected from nitrogen, oxygen and sulfur. Heterocyclo compounds include benzofused heterocyclic compounds such as benzo-1,4-dioxane. Such a moiety can be optionally substituted on one or more ring carbon atoms by halogen, hydroxy, hydroxycarbonyl, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., xe2x80x94NHxe2x80x94) of the ring by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a tertiary nitrogen atom (i.e., xe2x95x90Nxe2x80x94) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also attached to form a N-oxide[xe2x95x90N(O)xe2x80x94] group.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a 5- or 6-membered carbocyclic aromatic ring-containing moiety or a fused ring system containing two or three rings that have all carbon atoms in the ring; i.e., a carbocyclic aryl radical. Exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals.
The term xe2x80x9cheteroarylxe2x80x9d, alone or in combination means a 5- or 6-membered aromatic ring-containing moiety or a fused ring system (radical) containing two or three rings that have carbon atoms and also one or more heteroatoms in the ring(s) such as sulfur, oxygen and nitrogen. Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and the like), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, and the like), 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, and the like), quinoxalinyl, xcex2-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like radicals.
When an aryl or heteroaryl radical is a substituting moiety (group, substituent, or radical), it can itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocycloalkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino
wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,
wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group
wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
The term xe2x80x9caralkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like.
The term xe2x80x9caralkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the formula aralkyl-Oxe2x80x94C(O)xe2x80x94 in which the term xe2x80x9caralkylxe2x80x9d has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.
The term xe2x80x9caryloxyxe2x80x9d means a radical of the formula aryl-Oxe2x80x94 in which the term aryl has the significance given above. The phenoxy radical is an exemplary aryloxy radical.
The terms xe2x80x9cheteroaralkylxe2x80x9d and xe2x80x9cheteroaryloxyxe2x80x9d mean radicals structurally similar to aralkyl and aryloxy that are formed from heteroaryl radicals. Exemplary radicals include 4-picolinyl and 2-pyrimidinoxy, respectively.
The terms xe2x80x9calkanoylxe2x80x9d or xe2x80x9calkylcarbonylxe2x80x9d, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
The term xe2x80x9ccycloalkylcarbonylxe2x80x9d means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benzofused monocyclic cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.
The terms xe2x80x9caralkanoylxe2x80x9d or xe2x80x9caralkylcarbonylxe2x80x9d mean an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and the like.
The terms xe2x80x9caroylxe2x80x9d or xe2x80x9carylcarbonylxe2x80x9d means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.
The term xe2x80x9ccycloalkylalkoxycarbonylxe2x80x9d means an acyl group of the formula cycloalkylalkyl-Oxe2x80x94COxe2x80x94 wherein cycloalkylalkyl has the significance given above. The term xe2x80x9caryloxyalkanoylxe2x80x9d means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term xe2x80x9cheterocyclooxycarbonylxe2x80x9d means an acyl group having the formula heterocyclo-Oxe2x80x94COxe2x80x94 wherein heterocyclo is as defined above.
The term xe2x80x9cheterocycloalkanoylxe2x80x9d is an acyl radical of the formula heterocyclo-substituted alkane carboxylic acid wherein heterocyclo has the significance given above. The term xe2x80x9cheterocycloalkoxycarbonylxe2x80x9d means an acyl radical of the formula heterocyclo-substituted alkane-Oxe2x80x94COxe2x80x94 wherein heterocyclo has the significance given above. The term xe2x80x9cheteroaryloxycarbonylxe2x80x9d means an acyl radical represented by the formula heteroaryl-Oxe2x80x94COxe2x80x94 wherein heteroaryl has the significance given above.
The term xe2x80x9caminocarbonylxe2x80x9d (carboxamide) alone or in combination, means an amino-substituted carbonyl(carbamoyl) group derived from an amine reacted with a carboxylic acid wherein the amino (amido nitrogen) group is unsubstituted (xe2x80x94NH2) or a substituted primary or secondary amino group containing one or two substituents selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like, as recited. A hydroxamate is a N-hydroxycarboxamide.
The term xe2x80x9caminoalkanoylxe2x80x9d means an acyl group derived from an amino-substituted alkanecarboxylic acid wherein the amino group can be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d means fluoride, chloride, bromide or iodide. The term xe2x80x9chaloalkylxe2x80x9d means an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.
The term xe2x80x9cperfluoroalkylxe2x80x9d means an alkyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluoroalkyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
The term xe2x80x9cperfluoroalkoxyxe2x80x9d alone or in combination, means a perfluoroalkyl ether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkoxy groups, in addition to trifluoromethoxy (F3Cxe2x80x94Oxe2x80x94), are perfluorobutoxy, perfluoroisopropoxy, perfluorododecyloxy and perfluorodecyloxy.
The term xe2x80x9cperfluoroalkylthioxe2x80x9d alone or in combination, means a perfluoroalkyl thioether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkylthio groups, in addition to trifluoromethylthio (F3Cxe2x80x94Sxe2x80x94), are perfluorobutylthio, perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.
The term xe2x80x9caromatic ringxe2x80x9d in combinations such as substituted-aromatic ring sulfone or substituted-aromatic ring sulfoxide means aryl or heteroaryl as defined before.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering a compound corresponding in structure to Formula B that selectively inhibits one or more MMPs, while exhibiting less activity against at least MMP-1, in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition. A contemplated compound also does not substantially inhibit the production of TNF. The use of administration repeated a plurality of times is particularly contemplated. 
wherein R1, R2, R6, R7, R13, and R14 are as defined before.
A more preferred group of contemplated compounds for use in such a process corresponds in structure to Formula B1, below, 
wherein R1 and R14 are as defined before, and is a substituent selected from the group consisting of an alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aminoalkylcarbonyl, aminoaralkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, alkoxycarbonylaminoaralkylcarbonyl, cycloalkoxycarbonylaminoalkylcarbonyl, cycloalkoxycarbonylaminoaralkylcarbonyl, aryloxycarbonylaminoalkylcarbonyl, aryloxycarbonylaminoaralkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, aralkyloxycarbonylaminoalkylcarbonyl, heteroaryloxycarbonylaminoalkylcarbonyl and a heteroaryloxycarbonylaminoaralkylcarbonyl group.
A contemplated compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.
Also contemplated is the similar use of a contemplated compound in the treatment of a disease state that can be affected by the activity of metalloproteases such as TNF-xcex1 convertase. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used, where appropriate, in the form of an amine salt derived from an inorganic or organic acid. Exemplary acid salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.
Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl(C1-C6)halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C8-C20)halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.
Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
Total daily dose administered to a host mammal in single or divided doses of an MMP enzyme-inhibiting effective amount can be in amounts, for example, of about 0.001 to about 100 mg/kg body weight daily, preferably about 0.001 to about 30 mg/kg body weight daily and more usually about 0.01 to about 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should such dosing be desired by the person prescribing the drug.
The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
A compound useful in the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington""s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
A contemplated compound can be prepared by several routes of synthesis as can be seen from the specific Examples that follow. In addition, Schemes 1A and 1B, below, illustrate exemplary synthetic procedures and the use of preferred intermediates in the preparation of contemplated compounds.
Thus, as is seen in Scheme 1A, methyl N-acetylacrylate, compound 1, is reacted in a solvent such as methanol with p-fluorothiophenol in the presence of triethylamine at zero degrees C. via a Michael addition (step 1) and the resulting fluorophenylthioether is oxidized with Oxone(copyright) to form the corresponding sulfone, compound 2, in step 2. Hydrolysis of the methyl ester in glacial acetic acid containing hydrochloric acid at zero degrees C. provides the corresponding acid, compound 3. Reaction of compound 3 with thiophenol in DMF at about 10xc2x0 C. in the presence of potassium carbonate provides the thiophenylether, compound 4. The N-acetyl group is cleaved by reaction of compound 4 in glacial acetic acid and hydrochloric acid at 11xc2x0 C. to provide the amine hydrochloride, compound 5.
Reaction of compound 5 in water with an N-protected amino acid such ad CBZ-glycine (CBZ-Gly) in the presence of a water-soluble carbodiimide [1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride; EDC], 1-hydroxybenzotriazole (HOBT) and N-methylmorpholine (NMM) provides the corresponding N-aryloxycarbonylaminoalkylcarbonyl derivative, compound 6, that is shown in Scheme 1B. Reaction of compound 6 with O-tetrahydro-2H-pyran-2-yl-hydroxylamine in THF in the presence of HOBT and EDC provides the THP-protected hydroxamic acid, Compound 7. Reaction of compound 7 with an acid such as toluenesufonic acid of hydrochloric acid cleaves the THP protecting group to provide the hydroxamic acid, compound 8. 
The above syntheses, as with all of the reactions discussed herein, can be carried out under a dry inert atmosphere such a nitrogen, helium or argon if desired. Selected reactions known to those skilled in the art can be carried out under a dry atmosphere such as dry air, whereas other synthetic steps, for example, aqueous acid or base ester or amide hydrolyses, can be carried out under laboratory air.
In general, the choices of starting material and reaction conditions can vary as is well known to those skilled in the art. Usually, no single set of conditions is limiting because variations can be applied as required and selected by one skilled in the art. Conditions can also be selected as desired to suit a specific purpose such as small scale preparations or large scale preparations. In either case, the use of less safe or less environmentally sound materials or reagents is usually to be minimized. Examples of such less desirable materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzene and the like.
Various reactions illustrated in the above Scheme can be base-mediated by the use of catalytic amounts of some bases or carried out with an equivalent or more of a base by the addition of an additional reagent or the thiol reagent can be a preformed thiol salt such as the sodium salt of a thiophenol. Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary (Ixc2x0), secondary (IIxc2x0) or tertiary (IIIxc2x0) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides.
As non-limiting examples, such amines can include triethyl amine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N,Nxe2x80x2-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine and the like. Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiiospropyammonium hydroxide, tribenzyammonium hydroxide, dimethylbenzyl-ammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,Nxe2x80x2-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethyl-ammonium hydroxide, tetramethylammonium hydroxide, dimethyldiiospropylammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethylmorpholiniumhydroxide, N,N,Nxe2x80x2,Nxe2x80x2,-tetramethylpiperazeniumhydroxide, and N-ethyl-Nxe2x80x2-hexylpiperidinium hydroxide and the like.
Metal hydrides, amides or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like may also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl, phenyl or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadium reagents such as dimethylcadium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents.
The reaction media can comprise a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical non-protic solvents include acetone, tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride, hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea, N-methylpyrrolidone and the like.
Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making the products of this invention and the like.
Room temperature or less or moderate warming (xe2x88x9210xc2x0 C. to 60xc2x0 C.) are the preferred temperatures of the reaction. If desired, the reaction temperature can be about xe2x88x9276xc2x0 C. to the reflux point of the reaction solvent or solvents.
An intermediate thioether such as the 4-fluorophenylthio ether can be oxidized to the sulfone in one step using two equivalents to oxidizing agent. Reagents for this process can, in a non-limiting example, include peroxymonosulfate (OXONE(copyright)), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl hypochlorite, sodium hypochlorite, hypochlorus acid, sodium meta-peroiodate, periodic acid and the like. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water.
The oxidation can be carried out at temperature of about xe2x88x9278xc2x0 to about 50xc2x0 degrees centigrade, and normally is in a range of about xe2x88x9210xc2x0 C. to about 40xc2x0 C. Preparation of a desired sulfone can be carried out in a two-step process using about one quivalent of oxidizing agent to first form the sulfoxide at about 0xc2x0 C. A second oxidation then produces the sulfone.
The solvents listed above can be used with these selective oxidations with, for example, methanol or methanol/water being preferred along with a temperature of from about xe2x88x9210xc2x0 C. to 30xc2x0 C. It can be desirable in the case of more active oxidizing agents, but not required, that the reactions be carried out under an inert gas atmosphere with or without degassed solvents.
A hydroxamate can be prepared from the corresponding ester by reaction of the ester with one or more equivalents of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents such as those listed above. This exchange process can be further catalyzed by the addition of additional acid.
Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine in situ, which can exchange with an ester or amide. The exchange can be carried out with a protected hydroxylamine such as o-tetrahydro-2H-pyran-2-yl-hydroxylamine (tetrahydropyranylhydroxyamine; THPONH2), benzylhydroxylamine (BnONH2), and the like in which case compounds in which the ester is a tetrahydropyranyl (THP) or benzyl (Bn) ester.
Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage, is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group with an acid such as toluenesulfonic or hydrochloric acids or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon or nickel.
Oxidizable functional groups are readily recognized by those skilled in the art and alternative synthesis can be used such as the protection/deprotection sequence.
Acids can be converted into activated carbonyl compounds using reagents well known in the art including the peptide and protein synthesis and amino acid coupling or conjugation art. Examples of such reagents are thionyl chloride, oxalyl chloride, phosphorus oxychloride, 1-hydroxybenzotriazole (HOBT), isobutylchloroformate an the like. These valuable activated carbonyl intermediates can then be transformed into hydroxamic acids or hydroxamic acid derivatives such as H, benzyl or THP. Preparation of or interconversion between the hydroxylamine or hydroxylamine derivative compounds or acids or amides or esters can be carried out by one skilled in the art using the methods discussed above or by other techniques.
The amine function in the intermediate compounds use a protecting group to facilitate the transformations. Decisions involving the selection of protecting groups and their use can be made by a person skilled in the art. Especially useful are the techniques and reagents used in protein, peptide and amino acid coupling and transformation chemistry.
The use of the tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Z or CBZ) and N,N-dibenzyl groups as well as their synthesis and removal are examples of such protection schemes.
Coupling of the amino acids, amino acid esters, amino acid hydroxamates or hydroxamate derivatives and amino acid amides of the precursor (intermediate) compounds with, for example, other amino acids, amines, alcohols, amides or acids is also carried out by methods well known in the art such as, for example, active ester or mixed anhydride couplings with preferred bases if required being moderate tertiary amines such as N-methylmorpholine.
Removal of a preexisting group that can also serve as a protecting group or blocking group such as the acetyl group and the like is also accomplished using standard hydrolysis conditions such as base hydrolysis or exchange or acid exchange or hydrolysis.
In the case of compounds with an amine group, it is sometimes desirable to use acidic conditions with a reagent such as hydrogen peroxide and/or in combination with an acidic reagent such as periodic acid, peracetic acid and the like. It should also be noted by one skilled in the art that hydrolysis or exchange of the acetyl group may or may not effect hydrolysis or exchange of an ester, amide or hydroxamate function.
A selectively removable protecting group, P (R22), on the hydroxamate hydroxy group can also be utilized. Such protecting groups can include acyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, trisubstituted silyl groups and the like. Examples of such protecting groups include acetyl, THP, benzyl, Z, tert-butyldimethylsilyl (TBDMS) groups. The preparation of such protected hydroxamates as well as the removal of the protecting groups is well known in the art and its practitioners.
Compounds of this invention can be prepared by alkylation of a carbanion (nucleophile) generated from a protected carboxylic acid using processes known in the art. Protecting groups for the carboxyl function include, for example, esters such as tert-butyl esters. Bases for forming the anion are can be organometallic reagents such as tert-butyl lithium, metal amides such as lithium diisopopyl amide (LDA) or alkoxides such as potassium tert-butoxide. Other candidate bases are discussed above.
Following or during formation of the anion, the alkylating agent (electrophile) is added which undergoes a nucleophilic substitution reaction. Electrophilic substrates for displacement can include, for example, dihalo alkanes such as 1,2-dihaloalkanes or mono-halo-mono sulfated alkanes or bissulfonate alkane esters. 1,2-di-Bromoethanes, 1-chloro-2, bromoethanes, 1-chloro-2-tosylethanes and 1,2-di-toluenesulfonylethanes are examples of such bis-electrophiles. 1-Bromo-2-chloro-ethane is a preferred electrophile.
Activated ester groups are well known in the art and can include, for example, di-easters such as malonates, ester-ketones such as acetoacetic esters or ester-aldehydes that are subject to carbonyl addition reactions. Alkylation with one equivalent of alkylating agent followed by derivatization of the new omega carbonyl group with, for example, an organometallic reagent or reduction to form an alcohol which can then be derivatized to form a carbon halogen bonds or an activated ester such as a sulfate ester. These omega-substituted compounds can serve as substrates for the thioate displacement and oxidation reactions discussed above to form the carboxylic acid compounds or intermediates of this invention.
Omega-haloalcohols can be useful starting materials for the preparation of compounds of this invention using alternative synthetic sequences from those discussed above. They can serve as substrates for R1 thiolate displacement (SN2) to provide 4-sulfides (thio ethers) that can then be oxidized to the desired sulfones. The HSxe2x80x94R1 compounds can be prepared as discussed below and oxidized as discussed above. Preparation of the R1 group can be via an intermediate such as a fluorothiophenol followed by displacement of the fluoride with a second nucleophile to produce compounds or intermediates of this invention. Flourothiophenol and phenol and 2,3-dimethyl phenol are examples of preferred thiols and phenols, respectively. The sulfone alcohols can be oxidized to the corresponding carboxylic acids as well as to the corresponding aldehydes.
The preparation of ethers can be carried out by forming a salt of the alcohol and treating this nucleophile with an electrophile such as a halide or an activated ester such as a sulfate ester. The salt is formed by treating the alcohol with a base such as is discussed above. Examples of such bases are lithium alkyls, metal hydrides or the metal salts of an amine such as LDA.
Halides can be chlorides, bromides or iodides and sulfates can be, for example, benzene sulfonates, tosylates, mesylates or triflates. An example of a preferred electrophile is 2-chloromethylpyridine and a preferred base is sodium hydride. Alternatively, the alcohol can be converted into a leaving group (electrophilic reagent) and then treated with a nucleophile. Examples of such leaving groups include sulfate esters such tosylates, mesylates and triflates whose preparation is discussed above. The triflate is a preferred leaving group.
Displacement of these groups with nucleophiles is well known in the art and discussed and/or illustrated above. The nucleophiles can be hydroxide to allow inversion of stereochemistry, alkoxides to form ethers, amines or ammonia to form substituted amines or an azide anion to form an azide. A preferred nucleophile the is tetra-(n-butyl)ammonium azide. The azido compound, for example, can be reduced to form the amino acid.
Reductions are discussed above and are well known in the art. A preferred method is hydrogenation with palladium on carbon catalyst.
The amines, including the amino acids, of this invention can be acylated or alkylated by methods well known in the art. The amides formed can be considered as protected amines or as end products of this invention. Acylation to form such derivatives as tert-butoxycarbonyl and carbobenzyloxy carbonyl group is discussed above. Other acyl (Ac) groups can be, for example, acetyl, haloacetyl, aroyl, substituted aroyl, heteroaroyl, substituted heteroaroyl or other groups as required. The amines can be acylated using anhydrides, mixed anhydrides, acid chlorides or activated esters. Usually such acylations are carried out in presence of a base such as the bases discussed above and well known in the art. Examples are N-methyl-morpholine, triethylamine and the like.
The carboxyl compounds useful herein having amide substituents can be treated, converted or interconverted as shown and/or discussed above to form the products of this invention. In addition, the haloacetyl compounds such as the preferred 2-chloroacetamide derivative can be treated with an amine as a nucleophile to yield an amino acid. Again, these reactions are well known in the art. A preferred amine is morpholine.
Alkylation of the amino acid at the carbon alpha to the carbonyl group to form a useful compound can be carried out by first forming an anion using a base. Exemplary bases are discussed elsewhere. The preferred bases are strong bases that are either hindered and/or non-nucleophilic such as lithium amides, metal hydrides or lithium alkyls. A preferred base is lithium diisopropylamide (LDA) in a dipolar aprotic solvent or THF.
Following or during formation of the anion, an alkylating agent (an electrophile) is added which undergoes a nucleophilic substitution reaction. Non-limiting examples of such alkylating agents are 1,2-dihaloalkanes or haloalkanes also substituted by an activated ester group. Activated ester groups are well known in the art and can include, for example, an ester of a 2-halo-alcohol such as a bromo-, iodo- or chloro-ethane para-toluene sulfonate, triflate or mesylate. A preferred alkylating agents is 1-bromo-2-chloroethane.
The nitrogen substituent on the amino acid portion of the compounds of this invention can be varied. In addition, this can be accomplished at different stages in the synthetic sequence based on the needs and objectives of the skilled person preparing the compounds of this invention.
The N-side chain variations can include replacing the hydrogen (hydrido) substituent with a alkyl, arylalkyl, alkene or alkyne. This can be accomplished by methods well known in the art such as alkylation of the amine with an electrophile such as halo- or sulfate ester (activated ester) derivative of the desired side chain. This can be done in the presence of a base such as those discussed above and in a pure or mixed solvent as discussed above. A preferred base is potassium carbonate and a preferred solvent is DMF.
The alkenes and alkynes can be reduced, if desired, by, for example, hydrogenation with a metal catalyst and hydrogen, to an alkyl or arylalkyl compound of this invention and the alkyne or arylalkyne can be reduced to a alkene of alkane with under catalytic hydrogenation conditions as discussed above or with an deactivated metal catalyst. Catalysts can include, for example, Pd, Pd on Carbon, Pt, PtO2 and the like. Less robust catalysts include such thing as Pd on BaCO3 or Pd with quinoline or/and sulfur.
An alternative method for alkylation of the amine nitrogen is reductive alkylation. This process, well known in the art, allows treatment of the secondary amine with an aldehyde or ketone in the presence of a reducing agent such as borane, borane:THF, borane:pyridine, lithium aluminum hydride. Alternatively, reductive alkylation can be carried out hydrogenation conditions in the presence of a metal catalyst. Catalysts, hydrogen pressures and temperatures are discussed above and are well known in the art. A preferred reductive alkylation catalyst is borane:pyridine complex.
The compounds of this invention include compounds wherein the substituent on nitrogen of the amino acids as listed above provide amino acid carbamates. Non-limiting examples of these carbamates are the carbobenzoxycarbonyl (Z, CBZ, benzyloxycarbonyl), isobytoxycarbonyl and tert-butoxycarbonyl (BOC, t-BOC) compounds. These materials can be made, as discussed above, at various stages in the synthesis based on the needs and decisions made by a person skilled in the art using methods well known in the art.
Useful synthetic techniques and reagents include those used in protein, peptide and amino acid synthesis, coupling and transformation chemistry. The use of the tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (Z) as will as their synthesis and removal are examples of such protection or synthesis schemes discussed above. Transformations of amino acids, amino esters, amino acid hydroxamates, amino acid hydroxamate derivatives and amino acid amides of this invention or compounds used in this invention can be carried out as discussed and/or illustrated above. This includes, for example, active ester or mixed anhydride couplings wherein preferred bases, if required, are tertiary amines such as N-methylmorpholine.
Reagents for protection of the amine group of the protected amino acids include carbobenzoxy chloride, iso-butylchloroformate, tert-butoxycarbonyl chloride, di-tert-butyl dicarbonate and the like which are reacted with the amine in non-protic or dipolar aprotic solvents such as DMF or THF or mixtures of solvents. A preferred reagent is di-tert-butyl dicarbonate and a preferred solvent is THF. Further conversion of the cyclic amino acids of this invention including alkylation, displacement with a thiol or thiolate, oxidation to a sulfone, and conversion into a hydroxamic acid or hydroxamate derivative can be carried out discussed herein.
Sulfone compounds such as those where R1 is nitroaryl can be prepared as compounds of this invention by synthesis of a thiol or thiolate nucleophile, displacement of an electrophile (X) by the nucleophilic thiol or thiolate and oxidation of the product thia ether (sulfide) to the sulfone. For example, displacement of the electrophilic group X with a nitro-benzenethiol can yield a compound where R1 is nitrobenzene that can be reduced to provide a useful amino compound wherein R1 is an aniline that can be acylated to form a benzamido compound such as compounds 61-64 of Table 8, for example. It should be noted that nitrobenzenethiol is an example and not to be considered as limiting or required. Oxidation of the thioether product can be carried out as discussed below when desired.
The reduction of nitro groups to amines is well known in the art with a preferred method being hydrogenation. There is usually a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate and the like. Solvents can be protic or non-protic pure solvents or mixed solvents as required. The reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred. The amino group can be alkylated if desired, or acylated with, for example, an aroyl chloride, heteroaryl chloride or other amine carbonyl forming agent to form an R1 amide.
The amino sulfone or thioether can also be reacted with a carbonic acid ester chloride, a sulfonyl chloride, a carbamoyl chloride or an isocyanate to produce the corresponding carbamate, sulfonamides, or urea. Acylation of amines of this type are well known in the art and the reagents are also well known.
Usually, these reactions are carried out in aprotic solvents under an inert or/and dry atmosphere at about 45xc2x0 C. to about xe2x88x9210xc2x0 C. An equivalent of a non-competitive base is usually used with sulfonyl chloride, acid chloride or carbonyl chloride reagents. Following or before this acylation step, synthesis of the hydroxamic acid products of this invention can proceed as discussed.
Other thiol reagents can also be used in the preparation of compounds of this invention. Examples are fluoroaryl, fluoroheteroaryl, azidoaryl or azidoheteroaryl or heteroaryl thiol reagents. These thiols can be used a nucleophiles to as discussed above. Oxidation to the corresponding sulfone can then be carried out. The fluoro-substituted sulfone can be treated with a nucleophile such as ammonia, a primary amine, a quaternary ammonium or metal azide salt, under pressure if desired, to provide an azido, amino or substituted amino group that can then be reacted an activated benzoic or substituted benzoic acid derivative to form a benzamide. Azides can be reduced to an amino group using, for example, hydrogen with a metal catalyst or metal chelate catalyst or by an activated hydride transfer reagent. Hydrazo compounds can be oxidized to azo compounds and axo compounds can be reduced to hydrazo compounds. The amines can be acylated as discussed above.
Preferred methods of preparing aminethiol intermediates of this invention include protection of an aromatic or heteroaromatic thiol with trityl chloride to form the trityl thiol derivative, treatment of the amine with as reagent such as an aromatic or heteraromatic acid chloride to form the amide, removal of the trityl group, with acid to form the thiol. Preferred acylating agents include benzoyl chloride and preferred trityl removing reagents include triflouroacetic acid and trisiopropylsilane.
The fluorine on fluorosulfone intermediates can also be displaced with other aryl or heteroaryl nucleophiles for form compounds of this invention. Examples of such nucleophiles include salts of phenols, thiophenols, xe2x80x94OH group containing aromatic heterocyclic compounds or xe2x80x94SH containing heteroaryl compounds.
Tautomers of such groups azo, hydrazo, xe2x80x94OH or xe2x80x94SH are specifically included as useful isomers.
A preferred method of preparing intermediates in the synthesis of the substituted sulfones is by oxidation of an appropriate acetophenone, prepared from a flouroacetophenone, with for example, peroxymonosulfate, to form the corresponding phenol-ether. That phenol-ether is converted into its dimethylthiocarbamoyl derivative using dimethylthiocarbamoyl chloride, followed by rearranging the dimethylthiocarbamoyl derivative with heat to provide the thiol required for preparation of the thioether intermediate.
Salts of the compounds or intermediates of this invention are prepared in the normal fashion wherein acidic compounds are reacted with bases such as those discussed above to produce metal or nitrogen containing cation salts. Basic compounds such as amines can be treated with an acid to for form the amine salt. A preferred amine salt is the hydrochloride salt formed by reaction of the free base with HCl or hydrochloric acid.
Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes well known in the art, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent diastereoisomeric molecules, e.g., esters, amides, acetals, ketals, and the like, by reacting compounds of Formula I with an optically active acid in an activated form, a optically active diol or an optically active isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomericaly pure compound. In some cases hydrolysis to the parent optically active drug is not necessary prior to dosing the patient because the compound can behave as a prodrug. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials.
In addition to the optical isomers or potentially optical isomers discussed above, other types of isomers are specifically intended to be included in this discussion and in this invention.
Examples include cis isomers, trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers, tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substitution isomers are also included as isomers. Solvates or solvent addition compounds such as hydrates or alcoholates are also specifically included both as chemicals of this invention and in, for example, formulations or pharmaceutical compositions for delivery.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever.
Abbreviations are often used for reagents and solvents in the specific examples that follow. Those abbreviations and their meanings are as follows:
BOC=t-butoxycarbonyl
DEAD=diethyl azodicarboxylate
DMF=dimethylformamide
DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
EtOAc=ethyl acetate
EDC=1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride
Et2O=diethyl ether
HOBT=1-hydroxybenzotriazole
MeOH=methanol
MeCl2=methylene chloride
MsCl=methanesulfonyl chloride
NMMOL or NMM=N-methyl morpholine
THF=tetrahydrofruan
TsCl=toluenesulfonyl chloride
THP-O-hydroxylamine=O-tetrahydropyranhydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine
Z=carbobenzyloxycarbonyl